INDUCTION OF PROTECTIVE IMMUNITY TO LISTERIA IN NEONATES

描述(申请人提供)：单核细胞增多性李斯特菌(Lm)是新生儿的主要病原体。LM还被开发为从艾滋病毒到肿瘤的异种疫苗的疫苗载体。这些疫苗中的大部分将接种给婴儿。然而，关于新生儿或婴儿对LM的免疫反应几乎一无所知。这更令人惊讶，因为LM感染是免疫学研究最好的模型之一，已经产生了优秀的工具，允许解剖和有针对性地操纵成年小鼠宿主微生物在体内与它们对免疫的影响相互作用。我们相信，使用这些新可用的工具分析新生儿对LM感染的免疫反应将产生重要的机制见解，不仅对新生儿LM感染，而且对疫苗设计。 我们假设a)对LM感染提供保护性免疫的初级效应和记忆T细胞可以在新生儿中产生；b)主要是由于新生儿抗原提呈缺陷导致新生儿对原发LM感染的易感性增加；以及c)是新生儿特有的调节途径为新生儿对LM感染或疫苗接种而无法产生功能性记忆T细胞提供了机制基础。为了验证这些假设，我们将采用在成人LM感染和疫苗接种研究中成功采用的方法，并将这些工具应用于新生儿。与LM感染研究对成年小鼠免疫学知识的巨大影响类似，我们相信我们的研究将解决并揭示新生儿免疫学和疫苗学中的基本问题。

DESCRIPTION (provided by applicant): Listeria monocytogenes (LM) is a major pathogen in the neonate. LM is also being developed as a vaccine vehicle for heterologous vaccines from HIV to tumors. Most of these vaccines will be given to infants. Yet hardly anything is known about the immune response to LM in the neonate or infant. This is all the more surprising, as LM infection is one of the best-studied models in immunology, and excellent tools have been generated that have allowed the dissection and targeted manipulation of adult murine hostmicrobe in vivo interactions with their impact on immunity. We believe that an analysis of the neonatal immune response to LM infection employing these newly available tools will yield important mechanistic insights into not only neonatal LM infection, but also into vaccine design. We hypothesize a) that primary effector and memory T cells providing protective immunity to LM infection can be generated in the neonate; b) that it is mainly a deficit in neonatal antigen presentation that results in the neonate's heightened susceptibility to primary LM infection; and c) that it is neonate-specific regulatory pathways that provide the mechanistic underpinnings for the failure of functional memory T cell generation in the neonate in response to LM infection or vaccination. To test these hypotheses, we will take the approach successfully employed in the study of adult LM infection and vaccination, and apply these tools to the neonate. Similar to the tremendous impact the study of LM infection had on knowledge about immunology of the adult mouse, we believe our studies will address and bring to light fundamental issues in neonatal immunology and vaccinology.